Asparaginase Therapy in Pediatric Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is the most common cancer in pediatric patients, with an overall 5-year survival of >90%.¹ The length of treatment for these patients is typically 2 to 3 years and involves several phases (induction, consolidation, and maintenance) and multiple forms of chemotherapy.

Since the 1970s, asparaginase therapy has been an integral component in the treatment of ALL.² Leukemia cells are dependent on exogenous sources of asparagine for protein synthesis. The administration of asparaginase deprives the leukemia cells of asparagine, resulting in leukemic cell death.³ In the literature, complete depletion of asparagine is defined as an asparaginase activity level ≥0.1 IU/mL.^2,4

Asparaginase therapy is associated with various adverse effects, including pancreatitis, thrombosis, and hepatotoxicity. However, the major limitation to treatment is hypersensitivity reactions. The neutralization of asparaginase activity, known as silent inactivation, may also occur, with or without signs of hypersensitivity.⁵ Failure to receive the entire prescribed course of asparaginase therapy has been associated with poorer outcomes and higher rates of relapse in pediatric leukemia.² The possibility of developing a clinical allergy and silent inactivation may be determined by multiple factors, including the formulation, route of administration, schedule of administration, and the concurrent use of other chemotherapeutic agents.⁴

Types of Asparaginase Therapy

There are currently 3 formulations of asparaginase therapy available in the United States, which differ based on bacterial source and pharmacokinetic properties.

Escherichia coli (E coli)–derived L-asparaginase (Elspar; LASP) is an asparaginase preparation that was historically used beginning in the 1970s and is associated with high immunogenicity and increased hypersensitivity reactions.^2,5,6 E coli–derived LASP has a short half-life (8-30 hours), which requires a frequent administration schedule (3 times per week) to maintain adequate asparaginase activity.^2,4,5,7 Patients who developed a hypersensitivity reaction to E coli–derived LASP or who presented with a nadir asparaginase activity level <0.1 IU/mL were switched to a different formulation.^4,6 In 2012, the E coli–derived LASP formulation was discontinued in the US market.

Pegaspargase (Oncaspar; PEGASP) was first introduced as a second-line agent for patients who had a hypersensitivity reaction after E coli–derived LASP therapy, and is now considered the preferred first-line treatment.² This long-acting, PEGylated formulation of E coli–derived LASP has a longer half-life (5-8 days), which requires a less frequent administration schedule.^2,4,5,8 PEGASP achieves greater asparaginase activity levels and can be administered either intramuscularly (IM) or intravenously (IV).^2,9 In addition, it has a succinimidyl succinate linker that decreases the rates of antibody formation, therefore reducing the likelihood of allergic reactions.⁸ Hypersensitivity reactions are more likely to appear with an increasing number of administrations within the same cycle and after repeated doses of PEGASP 2500 IU/m². A patient may present with clinical hypersensitivity or a diagnosis of a silent inactivation, which prompts a switch to an alternative therapy.^2,4,5

Similar to PEGASP, calaspargase pegol (CALASP) is a PEGylated asparaginase with the same E coli–derived enzyme and polyethylene glycol moiety found in PEGASP. The difference is in the linker. The CALASP molecule is more stable due to its use of a succinimidyl carbonate linker, resulting in a long-acting agent that can be administered every 3 weeks.^8,10 Preclinical studies have confirmed that both PEGylated formulations have similar pharmacokinetic and pharmacodynamic properties and, thus, the incidence of hypersensitivity reactions and discontinuations due to allergic reaction are similar.¹⁰

In 2011, the first Erwinia asparaginase agent (Erwinaze), also called crisantaspase, was approved by the FDA as an alternative to E coli asparaginase.⁶ This shorter-acting formulation, derived from the Erwinia chrysanthemi bacteria, has a half-life of 4 to 22 hours.² Patients can receive asparaginase Erwinia chrysanthemi (ERWASP), as a 25,000 -IU/m² dose, administered IV over 1 hour every other day or IM on a Monday/Wednesday/Friday schedule for 2 consecutive weeks (6 doses replace 1 dose of PEGASP).^6,11

Addressing Asparaginase Shortages

Because ERWASP is the only alternative currently approved in the United States, the availability of this agent is crucial for continuing asparaginase therapy in patients who experience hypersensitivity reactions to the E coli–derived formulations. Unfortunately, since 2016 there have been multiple interruptions in the market availability of ERWASP due to manufacturing and quality issues.^12,13 A recent report from the Children’s Oncology Group (COG) evaluated the effects of incomplete asparaginase therapy in pediatric patients with acute B-cell ALL. Gupta and colleagues analyzed data from patients enrolled in COG trials AALL0031 and AALL0232 and found that disease-free survival was significantly decreased in National Cancer Institute–defined high-risk patients and in standard-risk patients classified as slow early responders.⁹

Given the evidence underlining the importance of complete asparaginase therapy and the inconsistent availability of ERWASP, alternative plans are being employed more frequently. In a recent informal survey of pediatric oncology pharmacists, all responders indicated that the ERWASP shortage has affected their practice in some way. Many treatment centers have implemented administering premedication regimens prior to PEGASP to reduce the incidence of reactions and therefore the need for an alternative asparaginase agent. Other changes made to the administration of PEGASP include extending the infusion time to 2 hours and concurrently administering additional hydration during the infusion. A number of institutions have attempted PEGASP desensitization using guidance from published experience or variations of those protocols. Because of these changes in administration, many institutions have begun analyzing asparaginase activity levels to ensure efficacy.

For patients who do react to E coli–derived asparaginase or who are unsuccessfully desensitized, clinicians have found it necessary to delay or omit ERWASP courses and make them up as they are able to, based on availability. Some institutions have opened the collaborative trial between Jazz Pharmaceuticals and COG at their sites for a new investigational agent, JZP-458 (commonly referred to as RC-P), as a treatment option in patients who have reacted to E coli–derived asparaginase and have not yet received an Erwinia asparaginase agent.

JZP-458 is a recombinant crisantaspase that is derived from a Pseudomonas fluorescens platform.¹³ A phase 1, randomized, open-label clinical trial was performed in healthy adult volunteers and confirmed a safety profile consistent with other asparaginase formulations, while also establishing dose levels that achieved the targeted serum asparaginase activity when administered IM and IV.¹³

An open-label, phase 2/3 clinical trial designed to determine efficacy and tolerability of RC-P in patients of all ages with ALL and lymphoblastic lymphoma opened in December 2019.¹⁴ This trial investigates the substitution of long-acting E coli–derived asparaginase products with RC-P in the treatment plans of those who have had either an allergic reaction or silent inactivation. The estimated study completion date is November 2021.

Conclusion

Asparaginase is an important addition to the backbone of therapy for pediatric patients with ALL. Hypersensitivity reactions and market instability continue to challenge the successful completion of all planned doses in treatment regimens for these patients. It is essential that new asparaginase products be developed, while also continuing to devise methods to prevent allergic reactions and inactivation of available asparaginase products to maximize the likelihood that patients will be able to receive all necessary doses.

References

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8. Angiolillo AL, Schore RJ, Devidas M, et al. Pharmacokinetic and pharmacodynamic properties of calaspargase pegol Escherichia coli L-asparaginase in the treatment of patients with acute lymphoblastic leukemia: results from Children’s Oncology Group study AALL07P4. J Clin Oncol. 2014;32:3874-3882.
9. Gupta S, Wang C, Raetz EA, et al. Impact of asparaginase discontinuation on outcome in childhood acute lymphoblastic leukemia: a report from the Children’s Oncology Group. J Clin Oncol. 2020;38:1897-1905.
10. Li R-J, Jin R, Liu C, et al. FDA approval summary: calaspargase pegol-mknl for treatment of acute lymphoblastic leukemia in children and young adults. Clin Cancer Res. 2020;26:328-331.
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12. Jazz Pharmaceuticals. Erwinaze supply. https://erwinazesupply.com/. Accessed January 31, 2021.
13. Lin T, Hernandez‐Illas M, Rey A, et al. A randomized phase 1 study of the safety, tolerability, and pharmacokinetics of recombinant Erwinia asparaginase (JZP-458) in healthy adult volunteers. Clin Transl Sci. 2020 Dec 5. Epub ahead of print.
14. ClinicalTrials.gov. An open-label study of JZP-458 (RC-P) in patients with acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL). https://clinicaltrials.gov/ct2/show/NCT04145531. Accessed January 28, 2021.